Derivative of estradiol and process of preparing it



Patented May 27, 1952 UNITED STATES mm ori ce 2,598,652-. j i DERIVATIVE F Es'm DijoL-nmi PRIGOE'S S" oF PREPARINGIT- I Leon yelluz ,andrGeorges lVIuller, Paris, France,

assignors to Les Laboratoires Francais de Chimiotherapie, Paris, France, a corporation of France No Drawing.

Application May 8, 1950, Serial No.

160,816. In France June 14, 1949 CH: CH

i C O-OH3 The new substance is a sex hormone useful in human and veterinary medicine.

It has been found that the new compound of the present invention may be obtained from ethinyl-estradiol of the structural formula:

CH3 OH -CECH by fixation of a molecule of water, the hydration being efiected in the presence of a catalyst, i. e. mercuric salt of para-toluene-sulfamide. Ethinyl-estradiol is a known substance described, for instance, in Ber. Chem. Ges., 1938, '71, 1024 or Naturwissenschaft 1938, 26, 96. Although it should be clearly understood that this invention is not limited to the preferred method of manufacturing the new compound which is the subject of the present invention, this method forms part of the invention and will be described in more detail and illustrated by an example.

The new product may be prepared by maintaining ethinyl-estradiol in alcoholic solution at the boiling point in the presence of mercuric salt of para-toluene-sulfamide. The resultant complex is then decomposed by an acid which allows isolation of the desired steroid. The process involves two steps, the preparation of the catalyst and the hydration proper, as will appear from the following example;

Preparation of the catalyst 2 grams of yellow mercuric oxide and 3.3 grams of para-toluene-sulfamide are ground together, then heated while agitated for 2 hours at 200 C, The gummy solid resulting from this treatment is then melted by heating it to a temperature of 2 205-210 C. for several minutes. The compact mass obtained by cooling the melted product is ground and treated four times with 20 cc. of boiling alcohol. By draining, 3.3 grams (65%) of catalyst is separated.

Hydration of ethinyl-estradiol 1 gram of ethinyl-estradiol (m. 182 C.) is heated at reflux for seven days with 2 grams of the above-described catalyst in 100 cc. of 95% ethyl alcohol. The reaction product is then cooled, filtered, the catalyst is washed in alcohol and the solvent distilled whereby finally 1.4 grams of residue is obtained. The catalyst is then treated anew with acetic acid whereby 0.5 grams of residue is separated from the reaction product, for a total of 1.9 grams of residue. This residue is then extracted by hot water in order to eliminate any catalyst it may still retain, then treated, while in the boiling water bath, by diluted hydrochloric acid, in the presence of benzene. The catalyst is now completely separated from the steroid which, in turn, is dissolved in the organic solvent, separated, washed in water, dried and distilled. There is obtained about 0.6 gram to of the new compound of this invention, melting successively at 216 and at 244 C. after recrystallization in benzene. Its optical rotation, measured with the sodium D line in acehaving an optical rotation of (a) I+35 in acetone solution.

2. In a process of hydrating ethinyl estradiol to 3,17-dihydroxy-l7-acetyl-A1,3,5-estratriene, the

2,598,662 r a 4 steps comprising'heating, to boiling, an alcoholic amide and separating the compound from theresolution of ethinyl estradiol in the presence of action mixture.

presence of mercuric salt of para-toluene-sulf:

mercuric salt of p-toluene suifonamide, until hy- LEON VELLUZ.

dration of said ethinyl estradiol is effected, deqEORGEs composing the resulting complex by acid treat- 5 V ment, and isolating the 3,1'7-dihydroxy-1'I-ace- REFERENCES CITED tyl'Al'3-5'estmtriene fOrmed- The following references are of record in the 3. A process for the preparation of 3,17-difile f this patent;

hydroxy-17-acety1 A1,3,5 estratriene comprising; r UNiTED STATES PATENTS thesteps of hydrating ethinyl-estradiol in the 10 v Number Name Date 2,280,236 'Inhofi'en Apr. 21, 1942 

1.AS A NEW COMPOUND, CRYSTALLINE 3,17, HYPHEN DIHYDROXY-17-ACETYL-$1,3,5-ESTRATIENE OF THE FORMULA 